The primary goal has been the elucidation of the structures of reactive metabolites which are responsible for the carcinogenic, cytotoxic, and mutagenic activity of benzo[a]pyrene and other polycyclic aromatic hydrocarbons. The approach taken consists of: i) synthesis of primary oxidative metabolites as well as selected secondary oxidative metabolites, ii) study of the metabolism of these hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for inherent mutagenicity of the synthetic metabolites toward bacterial and mammalian cells, iv) elucidation of the roles of the cytochrome P-450 cystem and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the rate of formation and nature of the products formed when reactive metabolites such as arene oxides and diol epoxides react with biopolymers and less complex model compounds, and vii) search for compounds capable of preventing the tumorigenic action of bay-region diol epoxides. Current chemical studies have included resolution and assignment of absolute configuration to benzo[c]-phenanthrene 5,6-oxide as well as the K-region trans dihydrodiols of nine polycyclic hydrocarbons. A novel method for complete 1H and 13C NMR assignment of complex hydrocarbons has been developed. Metabolism studies have shown that benzo[c]phenanthrene may be a weak carcinogen due to poor conversion to bay-region diol epoxides and that 7,12-dimethylbenz[a]anthracene is metabolized to its (5S,6R)-oxide in accord with theoretical predictions. Tumor studies on optically active, bay-region diol epoxides of benzo[c]phenanthrene have identified the (4R,3S)-diol-(2S,1R)-epoxide as the most potent carcinogenic metabolite of a hydrocarbon yet described. A new liver microsomal epoxide hydrolase has been characterized and shown to be selectively inactivated by a mechanism based inhibitor.